It is well known that many drugs taken orally, are destroyed on the first pass through the liver. It is also well known that when many drugs are taken orally, their rate of absorption into the body is not constant. In view of such difficulties, a number of different drug delivery systems have been developed.
The transdermal or transmucosal route for delivery of drugs provides many advantages, and transdermal or transmucosal systems for delivering a wide variety of drugs are described in U.S. Pat. Nos. 5,785,991; 4,764,381; 4,956,171; 4,863,970; 5,453,279; 4,883,660; 5,719,197 or EP patent application number 0 271 983; 0 267 617; 0 261 429; 0 526 561; as an example, some of which are mentioned hereinafter.
A major drawback of this therapy however, is the limitation of the amount of drug that can be transported across the skin, in many cases, drugs which would appear to be ideal candidates for transdermal delivery are found to have such low permeability through intact skin that they cannot be delivered in therapeutically effective amounts from transdermal devices. This limitation is due to several factors. Since the skin is a protective barrier by nature, the rates of transport of most compounds through the skin is quite slow. It is generally accepted that a surface of patch beyond 50-100 sqcm would result in difficulty of application. Therefore the application of a transdermal semisolid dosage form such as a gel, cream, ointment, liquid, etc., augments the patient's compliance and the surface of application can be extended.
In order to increase skin permeability so that drugs can be delivered in therapeutically effective amounts at therapeutically effective rates, it has been proposed different systems or devices or mechanisms one of which is deliver the drug(s) in presence of permeation enhancers. Usually, using penetration enhancing compounds, processes or devices to increase drug penetration solve this problem.
Various systems were suggested for this purpose, as described in different patents such as U.S. Pat. Nos. 5,785,991; 4,764,381; 4,956,171; 4,863,970; 5,453,279; 4,883,660; 5,719,197 or W.O. patents number 97/29735; 98/17316 or in the literature “Pharmaceutical Skin Penetration Enhancement”, J. Hadgraft, Marcel Dekker, Inc. 1993; “Tercutaneous Absorption”, R. Bronaugh, H. Maibach, Marcel Dekker, Inc. 1989, etc.
To be accepted, a permeation enhancer or a combination thereof should have the ability to enhance the permeability of the skin for the drug, should be non-toxic, non-irritant and non-sensitizing on repeated exposure.
It is often difficult to predict which compounds will work as permeation enhancers and which permeation enhancers will work for particular drugs. In transdermal drug delivery applications, a compound that enhances the permeability of one drug or a family of drugs may not necessarily enhance the permeability of another drug or family of drugs. That is also concluded after careful analysis of the scientific literature relating to this specific topics, such as “Transdermal Therapeutic Systemic Medications, Marcel Dekker Inc., New York, 1989” (see table on page 3).
Therefore, the usefulness of a particular compound(s) or mixture thereof as a permeation enhancer must be carefully analyzed and demonstrated by empirical work.
EPA 0 279 977 describes a transdermal device for administering progesterone and an estradiol ester alone or in combination, utilizing a polymer matrix which has the drug(s) with a penetration enhancer such as sucrose monococoate, glycerol monooleate, sucrose monolaurate, glycerol monolaureate, etc.
EPA 0 367 431 discloses that aliphatic alcohols such as isopropyl alcohol and isobutyl alcohol that are commonly used in topical transdermal formulation, thus, enhance the rate of transdermal delivery of steroid drugs.
WO 90/11 064 discloses a skin penetration enhancer composition. for transdermally administered pharmacologically active agents. The composition contains diethylene glycol monoethyl or monomethyl ether in addition to an ester component such as propylene glycol monolaurate, methyl laurate or the like.
U.S. Pat. No. 5,785,991 discloses a composition, device and method for transdermal administration of an active agent using a novel dual permeation enhancer mixture comprising lauryl acetate and a monoglyceride, glycerol monolaurate.
U.S. Pat. No. 4,764,381 discloses pharmaceutical preparations comprised of a pharmaceutically active ingredient and a carrier which comprises a percutaneous penetration enhancer comprised of 2-ethyl-1,3 hexanediol alone or in combination with oleic acid.
U.S. Pat. No. 4,863,970 discloses penetration-enhancing pharmaceutical compositions for topical transepidermal and percutaneous application which are non-irritating to the skin and describes a binary system of oleic acid or alcohol and a lower alcohol.
U.S. Pat. No. 5,453,279 describes an enhancing transdermal absorption composition useful in transdermal absorption of progestins including progesterone and optionally an estrogen for contraceptive or HRT. The enhancing composition comprise a combination of a lower alkyl ester of a polycarboxylic acid, an aliphatic monohydroxy alcohol and an aliphatic diol.
EP 0 526 561 B1 relates to the use of chemical penetration enhancers to enhance the transdermal delivery of medicaments through the skin, said chemical enhancers are alcohols.
None of the above mentioned inventions or publications report a study of lauryl alcohol together with diethylene glycol monoethyl ether in a ternary vehicle composite in a semisolid dosage form, designed to administer transdermally or through the mucosal membrane the group of active agents mentioned in the present invention. None of the above mentioned inventions or publications describe an adequate transdermal or transmucosal formulation to deliver therapeutic plasma levels of different types of active compounds, as it is disclosed in the present invention.
One object of the present invention is to obtain a transdermal formulation that could deliver, at controlled rates, an active compound or a mixture thereof, combined with appropriate permeation enhancers. As it is well described in the literature of the art, there is not obviousness regarding the use of penetration enhancers to administer a drug(s) by transdermal route. As it is mentioned by W. R. Pfister in its chapter on “Transdermal and Dermal Therapeutic Systems: Current Status” in “Transdermal and Topical Drug Delivery Systems”, Interpharm Press Inc., Buffalo Grove Ill., 1997, pages 33-112, no general guidelines exist that will ensure success in selecting an appropriate enhancer for a specific drug to be delivered from a transdermal device (Hsieh 1994). The science of optimizing topical formulations is not predictive from one drug to another and permeation enhancers can produce a wide range of enhancement factors across drugs having different physicochemical properties. Rather, this is a process that requires extensive experimental work.
It is also important to mention that transdermal permeability is mainly influenced by both physicochemical properties of the permeants and by the interaction of the permeants with the enhancers. Therefore a given enhancer could prove to be very adequate for a drug and simultaneously would not increase the permeability of the other compound. This is well illustrated by Chien, in its chapter on “Developmental Concepts and Practice in Transdermal Therapeutic Systems” in Transdermal Controlled Systemic Medications, Marcel Dekker Inc., New York, 1987, pages 25-81, who states that a penetration enhancer increases the permeation of different compound to different degree.
There has not been known an enhancer or combination thereof which shows the transdermal penetration enhancement effect for any active agent or drug. As an example we can quote results of this author as wherein below indicated:
Enhancement of skin permeability of variousdrugs by different types of enhancersEnhancement factor (a)PropylDecymethylDrugsmyristatePropyl oleateAzonesulfoxideProgesterone4.565.365.9611.04Estradiol9.3314.6220.1712.59Hydrocortisone4.575.0161.325.23Indomethacin3.774.6714.4915.67(a) Enhancement factor = (Normalized skin permeation rate) with enhancer/(Normalized skin permeation rate) without enhancer
Additionally, another argument in favor of our position is sustained when the results reported by Chien are analyzed. He published the dependence of the enhancement factor for the skin permeation of progesterone on the alkyl chain length of saturated fatty acid in “Transdermal Controlled Systemic Medications”. He found the major enhancement effect using caproic acid (C8), however the same author discloses in U.S. Pat. No. 5,145,682 that the better enhancer for estradiol is decanoic acid (C10). These results lead us to attain the same conclusion of Chien in “Transdermal Controlled Systemic Medications”, Marcel Dekker, New York 1987, pages 25-81, that concludes that the efficacy of skin penetration enhancer for a specific active agent, is function of the type, concentration and, how the penetration enhancer release from the devices.
The prior art presented herein clearly prove that at least for some compounds, as shown in the present patent application, there is no such an universal penetration enhancer composition and the adequate permeation rate across the skin can be achieved only by testing different types of compounds at different concentrations. Although prior art was useful for the theoretical approach, the results herein disclosed emerged from the careful investigation of multiple variables.